Bazedoxifene x acetate, 1-[[4-[2-(Hexahydro-1H-azepin-1-Dethoxy]phenyl]methyl]-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol monoacetate, is a third generation selective estrogen receptor modulator (SERM) that exhibits oestrogen-agonistic tissue-selective activity on the skeletal system and lipid metabolism while also acting as an oestrogen antagonist on breast and uterine tissue. Bazedoxifene x acetate was recently approved in the European Union for the treatment of postmenopausal osteoporosis in women at increased risk of fracture. It is marketed under the brand name Conbriza. The chemical structure of Bazedoxifene x acetate is shown in formula A:

Polymorphic forms of Bazedoxifene x acetate are disclosed in the prior art. For example, polymorphic form A of Bazedoxifene x acetate and methods of preparing the same are disclosed in U.S. Pat. No. 7,683,051. U.S. Pat. No. 7,683,052 relates to polymorphic form B of Bazedoxifene x acetate and methods of preparing the same. Methods of preparing polymorphic form A of Bazedoxifene x acetate are also described in US 2010/0016581, as well as a method of enhancing the stability of form A. US 2010/0016582 relates to methods of preparing polymorphic form A of Bazedoxifene x acetate.
According to U.S. Pat. No. 7,683,051 and U.S. Pat. No. 7,683,052, table 2, form A of Bazedoxifene x acetate shows higher solubility than form B in both, aqueous and organic solvent systems. Since it is well known that higher solubility can contribute to higher bioavailability, it is assumed that form A shows a higher bioavailability than form B. This is supported by the results of a bioequivalence study (3068A1-129-US) disclosed in the EMEA “assessment report for Conbriza” (EMEA/CHMP/660889/2008). Therefore, form A is preferably used for the preparation of a medicament.
According to U.S. Pat. No. 7,683,051 form A of Bazedoxifene x acetate is prepared by crystallization from alcohols. The crystallization temperature has to be kept at or below 20° C. according to U.S. Pat. No. 7,683,051 in order to obtain form A. At elevated temperatures e.g. at or above 25° C. the proportion of form B is increased according to U.S. Pat. No. 7,683,051. Furthermore, U.S. Pat. No. 7,683,052 describes a process for the preparation of polymorphic form B of Bazedoxifene x acetate by crystallization from alcohols at or above 25° C.
As described in the literature, form B of Bazedoxifene x acetate is the thermodynamically more stable form, whereas form A of Bazedoxifene x acetate is the kinetic (or meta-stable) form. Therefore, operating conditions and parameters such as crystallization temperature to get pure form A or pure form B of Bazedoxifene x acetate are critical, especially if the crystallization solvent for both polymorphs is identical as disclosed in U.S. Pat. No. 7,683,051 and U.S. Pat. No. 7,683,052.
US 2010/0016581 describes that form A of Bazedoxifene x acetate can easily convert to form B upon contact with a solvent or solvent mixture, for example ethylacetate and ethanol. However, the susceptibility of polymorphic form A of Bazedoxifene x acetate to conversion to alternate polymorph forms considerably affects its suitability for pharmaceutical compositions. US 2010/0016581 therefore suggests to keep polymorphic form A of Bazedoxifene x acetate in dry form in order to prevent undesired polymorphic transition.
In EMEA/CHMP/660889/2008 data for 29 batches of Bazedoxifene x acetate were reported, whereas the level of form II, which corresponds to form B of U.S. Pat. No. 7,683,052 is typically very low. EMEA/CHMP/660889/2008 further states that some of the clinical batches contained low levels of form II (form B of U.S. Pat. No. 7,683,052).
Because polymorphic form A of Bazedoxifene x acetate provides better bioavailability in drug formulations and because conventional preparation techniques require complicated and elaborate control of operating conditions and parameters, there is a need for a new simple and reliable process for the preparation of form A of Bazedoxifene x acetate in polymorphic pure form. The methods of preparing polymorphic pure form A of Bazedoxifene x acetate as described herein helps to meet these and other needs.